Insulin-like growth factor 1 (IGF-1) is a 70-amino acid polypeptide (molecular weight 7.6 kDa). IGF-1 is a member of a family of closely related growth factors with high homology to insulin that signal through a corresponding group of highly homologous tyrosine kinase receptors. IGF-1 is produced by many tissues, but the liver is the main source of circulating IGF-1. IGF-1 is the major mediator of the anabolic and growth-promoting effects of growth hormone (GH). IGF-1 is transported by IGF-binding proteins, in particular insulin-like growth factor binding protein 3 (IGFBP-3), which also controls its bioavailability and half-life. Noncomplexed IGF-1 and IGFBP-3 have short half-lives (t1/2) of 10 and 30 to 90 minutes, respectively, while the IGFBP-3/IGF-1 complex is cleared with a much slower t1/2 of 12 hours.

IGFBP-3 is a 264-amino acid peptide (MW 29kD) produced by the liver. It is the most abundant of a group of IGFBPs that transport, and control bioavailability and half-life of IGFs, in particular IGF-1, the major mediator of the anabolic- and growth-promoting effects of GH. Noncomplexed IGFBP-3 and IGF-1 have short half-lives (t1/2) of 30 to 90 minutes, and 10 minutes, respectively, while the IGFBP-3/IGF-1 complex is cleared with a much slower t1/2 of 12 hours. In addition to its IGF binding-function, IGFBP-3 also exhibits intrinsic growth-regulating effects that are not yet fully understood, but have evoked interest with regards to a possible role of IGFBP-3 as a prognostic tumor marker.

The secretion patterns of IGF-1 and IGFBP-3 mimic each other, their respective syntheses being controlled by GH. Unlike GH secretion, which is pulsatile and demonstrates significant diurnal variation, IGF-1 and IGFBP-3 levels show only minor fluctuations. IGF-1 and IGFBP-3 serum levels therefore represent a stable and integrated measurement of GH production and tissue effect.

Low IGF-1 and IGFBP-3 levels are observed in GH deficiency or GH resistance. If acquired in childhood, these conditions result in short stature. Childhood GH deficiency can be an isolated abnormality or associated with deficiencies of other pituitary hormones. Some of the latter cases may be due to pituitary or hypothalamic tumors, or result from cranial radiation or intrathecal chemotherapy for childhood malignancies. Most GH resistance in childhood is mild-to-moderate, with causes ranging from poor nutrition to severe systemic illness (eg, renal failure). These individuals may have IGF-1 and IGFBP-3 levels within the reference range. Severe childhood GH resistance is rare and usually due to GH-receptor defects. Both GH deficiency and mild-to-moderate GH resistance can be treated with recombinant human GH (rhGH) injections. The prevalence and causes of adult GH resistance are uncertain, but adult GH deficiency is seen mainly in pituitary tumor patients. It is associated with decreased muscle bulk and increased cardiovascular morbidity and mortality, but replacement therapy remains controversial.

Elevated serum IGF-1 and IGFBP-3 levels indicate a sustained overproduction of GH, or excessive rhGH therapy. Endogenous GH excess is caused mostly by GH-secreting pituitary adenomas, resulting in gigantism, if acquired before epiphyseal closure, and in acromegaly thereafter. Both conditions are associated with generalized organomegaly, hypertension, diabetes, cardiomyopathy, osteoarthritis, compression neuropathies, a mild increase in cancer risk (breast, colon, prostate, lung), and diminished longevity. It is plausible, but unproven, that long-term rhGH overtreatment may result in similar adverse outcomes.

Malnutrition results in low IGF-1 levels, which recover with restoration of adequate nutrition.

Both insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) measurements can be used to assess growth hormone (GH) excess or deficiency. However, for all applications, IGF-1 measurement has generally been shown to have superior diagnostic sensitivity and specificity, and should be used as the primary test. In particular, in the diagnosis and follow-up of acromegaly and gigantism, IGFBP-3 measurement adds little if anything to IGF-1 testing. The combination of IGF-1 and IGFBP-3 measurements appears superior to determining either analyte alone in the diagnosis of GH deficiency and resistance, and in the monitoring of recombinant human GH therapy.

IGF-1 and IGFBP-3 levels below the 2.5th percentile for age are consistent with GH deficiency or severe GH resistance, but patients with incomplete GH deficiency or mild-to-moderate GH resistance may have levels within the reference range. In GH deficiency, GH levels may also be low and can show suboptimal responses in stimulation tests (eg, exercise, clonidine, arginine, ghrelin, growth hormone-releasing hormone, insulin-induced hypoglycemia), while in severe GH resistance, GH levels are substantially elevated. However, dynamic GH testing is not always necessary for diagnosis. If it is undertaken, it should be performed and interpreted in endocrine testing centers under the supervision of a pediatric or adult endocrinologist.

The aim of both pediatric and adult GH replacement therapy is to achieve IGF-1 and IGFBP-3 levels within the reference range, ideally within the middle-to-upper third. Higher levels are rarely associated with any further therapeutic gains, but could potentially lead to long-term problems of GH excess.

Elevated IGF-1 and IGFBP-3 levels support the diagnosis of acromegaly or gigantism in individuals with appropriate symptoms or signs. In successfully treated patients, both levels should be within the normal range, ideally within the lower third. In both diagnosis and follow-up, IGF-1 levels correlate better with clinical disease activity than IGFBP-3 levels.

Increased concentrations of IGF-1 are normal during pregnancy however reference ranges on this population have not been formally established in our institution.

After transsphenoidal removal of pituitary tumors in patients with acromegaly, IGF-I concentration starts to decrease and returns to normal levels in most patients postoperatively by the fourth day.(1)

Persons with anorexia or malnutrition have low values of IGF-1. IGF-1 is a more sensitive indicator than prealbumin, retinol-binding protein, or transferrin for monitoring nutritional repletion.

Puberty onset, ie the transition from Tanner stage 1 (prepubertal) to Tanner stage 2 (early pubertal), occurs for girls at a median age of 10.5 (+/-2) years and for boys at a median age of 11.5 (+/-2) years. There is evidence that it may occur up to 1 year earlier in obese girls and in African-American girls. By contrast, for boys there is no definite proven relationship between puberty onset and body weight or ethnic origin. Progression through Tanner stages is variable. Tanner stage 5 (young adult) should be reached by age 18.

Insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3) reference ranges are highly age dependent and results must always be interpreted within the context of the patient's age.

Discrepant IGF-1 and IGFBP-3 results can sometimes occur due to liver and kidney disease; however, this is uncommon and such results should alert laboratories and physicians to the possible occurrence of a preanalytical or analytical error.

Currently, IGF-1 or IGFBP-3 IGF-1 cannot be reliably used as risk indicators or prognostic markers in breast, colon, prostate, or lung cancer.

IGF-1 and IGFBP-3 assays exhibit significant variability among platforms and manufacturers. Direct comparison of results obtained by different assays is problematic. Rebaselining of patients is preferred if assays are changed.

Heterophile antibodies in human serum can react with the immunoglobulins included in the assay components causing interference with immunoassays. Specimens from patients with autoimmune diseases or from individuals routinely exposed to animals or animal serum products can demonstrate this type of interference, potentially causing an anomalous result. The assay reagents have been formulated to minimize the risk of such interference; however, rare interactions can occur. For diagnostic purposes, the results obtained from this assay should always be used in combination with the clinical examination, patient medical history, and other findings.

Reference values have not been established for patients that are >90 years of age.

IGF-1 reference values according to Tanner stages I-V(2)

Males

Stage I: 83-255 ng/mL

Stage II: 114-440 ng/mL

Stage III: 236-516 ng/mL

Stage IV: 218-580 ng/mL

Stage V: 229-522 ng/mL

Females

Stage I: 90-324 ng/mL

Stage II: 104-456 ng/mL

Stage III: 249-519 ng/mL

Stage IV: 238-574 ng/mL

Stage V: 187-509 ng/mL

Note: Puberty onset, ie the transition from Tanner stage 1 (prepubertal) to Tanner stage 2 (early pubertal), occurs for girls at a median age of 10.5 (+/-2) years and for boys at a median age of 11.5 (+/-2) years. There is evidence that it may occur up to 1 year earlier in obese girls and in African-American girls. By contrast, for boys there is no definite proven relationship between puberty onset and body weight or ethnic origin. Progression through Tanner stages is variable. Tanner stage 5 (young adult) should be reached by age 18.

INSULIN-LIKE GROWTH FACTOR BINDING PROTEIN 3

1-7 days: < or =0.7 mcg/mL

8-14 days: 0.5-1.4 mcg/mL

15 days-11 months: unavailable

1 year: 0.7-3.6 mcg/mL

2 years: 0.8-3.9 mcg/mL

3 years: 0.9-4.3 mcg/mL

4 years: 1.0-4.7 mcg/mL

5 years: 1.1-5.2 mcg/mL

6 years: 1.3-5.6 mcg/mL

7 years: 1.4-6.1 mcg/mL

8 years: 1.6-6.5 mcg/mL

9 years: 1.8-7.1 mcg/mL

10 years: 2.1-7.7 mcg/mL

11 years: 2.4-8.4 mcg/mL

12 years: 2.7-8.9 mcg/mL

13 years: 3.1-9.5 mcg/mL

14 years: 3.3-10 mcg/mL

15 years: 3.5-10 mcg/mL

16 years: 3.4-9.5 mcg/mL

17 years: 3.2-8.7 mcg/mL

18 years: 3.1-7.9 mcg/mL

19 years: 2.9-7.3 mcg/mL

20 years: 2.9-7.2 mcg/mL

21-25 years: 3.4-7.8 mcg/mL

26-30 years: 3.5-7.6 mcg/mL

31-35 years: 3.5-7.0 mcg/mL

36-40 years: 3.4-6.7 mcg/mL

41-45 years: 3.3-6.6 mcg/mL

46-50 years: 3.3-6.7 mcg/mL

51-55 years: 3.4-6.8 mcg/mL

56-60 years: 3.4-6.9 mcg/mL

61-65 years: 3.2-6.6 mcg/mL

66-70 years: 3.0-6.2 mcg/mL

71-75 years: 2.8-5.7 mcg/mL

76-80 years: 2.5-5.1 mcg/mL

81-85 years: 2.2-4.5 mcg/mL

Tanner Stages:

Males

Stage I: 1.2-6.4 mcg/mL

Stage II: 2.8-6.9 mcg/mL

Stage III: 3.9-9.4 mcg/mL

Stage IV: 3.3-8.1 mcg/mL

Stage V: 2.7-9.1 mcg/mL

Females

Stage I: 1.4-5.2 mcg/mL

Stage II: 2.3-6.3 mcg/mL

Stage III: 3.1-8.9 mcg/mL

Stage IV: 3.7-8.7 mcg/mL

Stage V: 2.6-8.6 mcg/mL

Note: Puberty onset, ie the transition from Tanner stage 1 (prepubertal) to Tanner stage 2 (early pubertal), occurs for girls at a median age of 10.5 (+/-2) years and for boys at a median age of 11.5 (+/-2) years. There is evidence that it may occur up to 1 year earlier in obese girls and in African-American girls. By contrast, for boys there is no definite proven relationship between puberty onset and body weight or ethnic origin. Progression through Tanner stages is variable. Tanner stage 5 (young adult) should be reached by age 18.